Spleen tyrosine kinase (Syk) plays an essential role in the signal transduction of immunoreceptor tyrosine-based activation motifs (ITAM) and the activation of immune cells. R788 disodium is a prodrug of R406, which selectively inhibits Syk with IC50 value of 41 nM. The inhibitory effect of R406 was observed in several Syk-dependent pathways. R406 at 0.001 - 10 μM inhibited anti-IgG-induced degranulation of cultured human mast cells at a dose-dependent manner. It also inhibited the production of TNF-induced by FcγR-crossing-linking in human macrophages. In primary B cells isolated from human peripheral blood, R406 effectively inhibited the upregulation of cell surface CD69 stimulated by B-cell receptor-cross-linking with anti-IgM[4]. In a Eμ-T-cell leukemia 1 (TCL1) mouse model of chronic lymphocytic leukemia (CLL), injection of R788 (80 mg/kg/day) from days 4 to 25 significantly prevented the outgrowth of the leukemia compared to non-treated group. R788 treatment also significantly elevated the survival rate in these treated animals. In B6/C3H mice with overt TCL1-002 leukemia, 15-day treatment of R788 suppressed the increase of circulating leukemic cells seen in control group. Moreover, R788-trreated mice demonstrated significantly reduced amount of phosphorylated SykYY525/526, BLNK, and ERK in leukemic cells, indicating the inhibition of B-cell receptor signaling pathway in vivo[5].
作用机制
R788 disodium is a prodrug of R406, which inhibits the activity of Sky kinase as an ATP-competitive inhibitor with a Ki value of 30 nM[4].
Fostamatinib Disodium/福他替尼二钠盐 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Neutrophils
1 µM
1 hour
To evaluate the effect of R406 on LPS-induced degranulation and cytokine release in neutrophils, results showed that R406 significantly reduced degranulation but had minimal impact on cytokine release
Cell Immunol. 2024 Sep-Oct;403-404:104860.
Mouse platelets
1 µM
10 minutes
To validate the inhibitory effect of Fostamatinib on platelet signaling, results showed that R406 significantly reduced the activation of Syk and Src family kinases.
Front Immunol. 2023 Dec 21;14:1285345.
Healthy donor washed human platelets
10 µM
10 minutes
R406 completely abolished the tyrosine phosphorylation of Syk, LAT, and PLCγ2 induced by atherosclerotic plaque homogenate and blocked upstream Src Y418 autophosphorylation at 10 µM concentration.
Int J Mol Sci. 2022 Jun 23;23(13):6982.
Healthy donor washed human platelets
3 µM
10 minutes
R406 at 3 µM concentration significantly inhibited platelet aggregation in response to 70 µg/mL of plaque homogenate and completely blocked platelet aggregation in washed platelets at 10 µM concentration.
Int J Mol Sci. 2022 Jun 23;23(13):6982.
Neutrophils
0.25, 0.5, 1 µM
2 hours
Reduced LPS-induced neutrophil activation and ROS release
J Inflamm Res. 2024 Nov 25;17:9757-9771.
BMDMs
500 nM
24 hours
To study the effect of Syk inhibitor R788 on BMDMs, results showed that R788 downregulated the expression of immunosuppressive genes.
Cancer Res. 2023 Aug 15;83(16):2675-2689.
Healthy donor washed human platelets
10 µM
30 minutes
R406 at 10 µM concentration reduced platelet adhesion on atherosclerotic plaque under static conditions but did not affect the platelet surface area.
Int J Mol Sci. 2022 Jun 23;23(13):6982.
THP-1 cells
10-20 µM
4 hours
To evaluate the inhibitory effect of Fostamatinib on TBK1 phosphorylation. The results showed that Fostamatinib significantly inhibited the phosphorylation levels of TBK1 and IRF3.
BMC Med. 2024 Mar 5;22(1):96.
Peritoneal macrophages
1 µM
6 hours
Inhibited LPS-induced mRNA transcription of TNF-α, IL-6, CCL2, CCL3, and CXCL10
J Inflamm Res. 2024 Nov 25;17:9757-9771.
Neutrophils
1 µM
8 hours
To evaluate the effect of R406 on LPS-induced NETosis in neutrophils, results showed that R406 effectively inhibited NETosis
Cell Immunol. 2024 Sep-Oct;403-404:104860.
NSC-34 cells
10 µM
To evaluate the inhibitory effect of Fostamatinib on the cGAS/STING signaling pathway induced by ALS-related toxic proteins. The results showed that Fostamatinib significantly inhibited the phosphorylation of TBK1 and IRF3.
BMC Med. 2024 Mar 5;22(1):96.
Fostamatinib Disodium/福他替尼二钠盐 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Rats
Conscious and anaesthetized rats
Oral
10, 30, 100 mg/kg
Single dose, up to 24 hours
Fostamatinib dose-dependently increased blood pressure, and the time course of the BP effect correlated closely with the plasma concentrations of R406
Br J Pharmacol. 2014 May;171(9):2308-20
C57/B6 mice
Pancreatic cancer model
Intraperitoneal injection
50 mg/kg
Five times per week, until tumor harvest
To study the effect of R788 alone or in combination with Gem on pancreatic cancer tumor growth and metastasis, results showed that R788 significantly reduced tumor size and metastatic nodules.
Cancer Res. 2023 Aug 15;83(16):2675-2689.
C57BL/6 mice
LPS-induced SIRS model
Oral
7.5, 15, 30 mg/kg
Once daily for 3 days
Reduced LPS-induced inflammatory factor levels and inhibited excessive consumption of neutrophils in bone marrow
J Inflamm Res. 2024 Nov 25;17:9757-9771.
Mice
Ferric chloride-induced carotid artery thrombosis model
Oral
80 mg/kg
Single dose
Fostamatinib did not significantly affect arterial thrombus formation in mice.
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